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United States Patent |
5,149,368
|
Liu
,   et al.
|
September 22, 1992
|
Resorbable bioactive calcium phosphate cement
Abstract
This invention provides a calcium phosphate cement with relatively high
surface pH which is very beneficial from the biocompatibility point of
view. When calcium phosphate salts react with an acidic reagent to form
cement, it normally involves the dissolution and recrystallization
process. The acidity of the setting cements depends strongly on the nature
of the calcium phosphate salt used, the acidity of the setting reagent,
and the reaction rate. The present invention uses high alkaline calcium
phosphate ceramics such as tetracalcium phosphate alone or together with
calcium phosphate ceramics such as .alpha.-tricalcium phosphate as base
cementing powder to increase the surface pH of the setting cement.
Inventors:
|
Liu; Sung-Tsuen (29 Landing, Laguna Niguel, CA 92677);
Chung; Harvey H. (43 Via Costa Verde, Rancho Palos Verdes, CA 90274)
|
Appl. No.:
|
639536 |
Filed:
|
January 10, 1991 |
Current U.S. Class: |
424/602; 106/35; 501/1 |
Intern'l Class: |
C09K 003/00 |
Field of Search: |
501/1
623/16
106/35
433/228.1
|
References Cited
U.S. Patent Documents
4668295 | May., 1987 | Bajpai | 106/85.
|
Primary Examiner: Group; Karl
Assistant Examiner: Gallo; Chris
Attorney, Agent or Firm: Drucker & Sommers
Claims
I claim:
1. A cementitious paste for orthopaedic, dental and maxillofacial
applications comprising:
a cementing powder of tetracalcium phosphate;
a setting reagent consisting essentially of an acidic citrate, wherein the
weight ratio of cementing powder to setting reagent lies between 2:1 and
15:1; and
sufficient water to form said paste, and which paste, after setting has a
pH greater than 5.
2. The paste of claim 1, wherein said cementing powder is fully decomposed
hydroxyapatite which contains tetracalcium phosphate and
.alpha.-tricalcium phosphate.
3. The paste of claim 1, wherein said acidic citrate is selected from the
group consisting of citric acid, NaH.sub.2 citrate, Na.sub.2 H citrate,
KH.sub.2 citrate, K.sub.2 H citrate, (NH.sub.4).sub.2 H citrate and
NH.sub.4 H.sub.2 citrate salt.
4. The paste of claim 1, further comprising soluble pH adjusting reagents.
5. The paste of claim 4 wherein the soluble pH adjusting reagents are
selected from the group consisting of NaOH, KOH, NH.sub.4 OH, Na.sub.3
citrate, K.sub.3 citrate, (NH.sub.4).sub.3 citrate, Na.sub.3 PO.sub.4,
Na.sub.2 HPO.sub.4, K.sub.3 PO.sub.4 or K.sub.2 HPO.sub.4.
6. The paste of claim 5 wherein the soluble pH adjusting reagents are
premixed with said cementing powder and setting reagent.
7. The paste of claim 5 wherein the soluble pH adjusting reagents are
dissolved in the water.
8. The paste of claim 1 further including up to approximately 85% by weight
of an inert filler.
9. The paste of claim 8 wherein the inert filler is selected from the group
consisting of .alpha.-tricalcium phosphate, calcium phosphate, dicalcium
phosphate, octacalcium phosphate, calcium carbonate, calcium sulfate
dihydrate, calcium sulfate hemihydrate, calcium sulfate anhydrous, calcium
oxide, calcium hydroxide, calcium fluoride, calcium citrate, magnesium
oxide, and magnesium hydroxide.
10. The paste of claim 9 wherein the inert filler is of a particle size
ranging from 1 micron to 20 mesh.
11. The paste of claim 1, wherein said water is saline.
12. The paste of claim 1 further including up to approximately 30% of an
antibiotic.
13. The paste of claim 1 further including up to approximately 30% bone
morphological protein.
14. The paste of claim 1 wherein the cementing powder contains partially
decomposed hydroxyapatite which contains .alpha.-tricalcium phosphate and
tetracalcium phosphate as a major component and undecomposed
hydroxyapatite as a minor component.
Description
BACKGROUND OF THE INVENTION
1. FIELD OF THE INVENTION
This invention relates to bioresorbable cement setting reagents
particularly to those formed from calcium phosphates, and useful in dental
and bone cements, bone graft materials, bone substitutes, bone fillers, as
a drug release carrier, and in other medical applications.
2. DESCRIPTION OF THE PRIOR ART
The major inorganic constituent of hard tissue is biological apatite. For
example, bone has 65% to near 70% of biological apatite, and teeth contain
more than 98% biological apatite. Hydroxyapatite is a calcium phosphate
compound which has same crystal structure as biological apatite. In
principle, hydroxyapatite should be an ideal candidate as hard tissue
replacement material. However, the precipitated hydroxyapatite has very
fine particle size. Because of manipulation requirements, this hinders the
applications of precipitated hydroxyapatite in the medical area. In the
last twenty years or so, many types of calcium phosphate ceramics have
been prepared. Among these, hydroxyapatite and 62 -tricalcium phosphate
ceramics and calcium phosphate containing glass have been extensively
studied. Clinical studies confirmed that most of the calcium phosphate
ceramics such as hydroxyapatite, tricalcium phosphate, tetracalcium
phosphate and dicalcium phosphate have excellent biocompatibility and can
be well accepted by both hard tissue and soft tissue. The experimental
results also indicated that dense hydroxyapatite is non-bioresorbable
while other porous calcium phosphate ceramics are bioresorbable.
Calcium phosphate ceramics have been approved as useful and biocompatible
materials for bone substitutes. These include dicalcium phosphate,
tricalcium phosphate, apatite compounds and tetracalcium phosphate. Most
of the calcium phosphate ceramics for medical application are prepared
either as granule form or block form. The granule form has a mobility
problem while the block form is very brittle and is difficult to shape. In
order to solve the above problems, many attempts have been made to prepare
bioresorbable grouts or cementing materials. Among these are Plaster of
Paris, collagen and several types of calcium phosphate cement.
Ideally, a useful cementing material for hard tissue application should
have good biocompatibility, suitable bioresorption rate, and good setting
character with reasonable setting time. Most of the above materials have
certain disadvantages. Plaster of Paris have reasonable setting character
but the resorption rate is too fast. Collagen-hydroxyapatite composite and
polylactate-HA composite can serve as useful delivery system for
hydroxyapatite granule. However, these materials can only be made as
premolded shape and cannot be molded at the surgical site. Polyacrylic
acid calcium phosphate cement is not bioresorbable and the setting cement
is too acidic.
Recently, a calcium phosphate cement with bi-functional organic acids or
amino acids has been reported (U.S. Pat. No. 4,668,295). However, this
cement is also very acidic and disintegrates very fast in the liquid
environment. It has been noted that in practice such a cement gives a low
pH product which can be irritating and not well tolerated. No ingredients
that would raise the pH closer to neutral are disclosed therein.
Pure hydroxyapatite cement prepared by reacting tetracalcium phosphate and
other calcium phosphate is not resorbable and does not have good setting
character (U.S. Pat. Nos. 4,518,430 and 4,612,053). An octacalcium
phosphate cement prepared by reacting hydroxyapatite and dicalcium
phosphate has also been reported Oonishi.sup.1 studied the
.alpha.-tricalcium phosphate bioactive cement using citric acid as setting
reagent. The cement has reasonable setting time and strong mechanical
strength However, the cement is very acidic in nature. More, recently a
calcium phosphate containing bioglass cement using phosphoric acid or
calcium hydroxide as setting reagent has been reported by E. A.
Monroe.sup.2 and his co-workers.
.sup.1 "Studies on Development of .alpha.-TCP Bioactive Bone Cement" H.
Oonishi, et al, Osaka-Minami National Hospital.
.sup.2 Abstract Phosphate Glass Bone Graft. Published at the 15th Annual
Meeting of the Society for Biomaterials April 28, May 2, 1989 Lake Buena
Vista, Fla., U.S.A.
The development of moldable bioresorbable calcium phosphate cement would
expand the medical application of calcium phosphate ceramics considerably.
Most of the previous calcium phosphate cements developed used
hydroxyapatite and tricalcium phosphate as cementing powder, and used
acids such as phosphoric acid, bi-functional organic acids, citric acid or
polyacrylic acid. These cements are normally very acidic in nature and
take a very long time for them to reach neutral pH. After implantation,
these cements would cause irritation and inflammatory reaction. Beside,
these cements are difficult to control the setting time and do not have
good manipulation characteristics.
SUMMARY OF THE INVENTION
This invention provides a calcium phosphate cement with relatively high
surface pH which is very beneficial from the biocompatibility point of
view. When calcium phosphate salts react with an acidic reagent to form
cement, it normally involves the dissolution and recrystallization
process. The acidity of the setting cements depends strongly on the nature
of the calcium phosphate salt used, the acidity of the settling reagent,
and the reaction rate. The present invention uses a high alkaline calcium
phosphate ceramic such as tetracalcium phosphate alone or together with a
calcium phosphate ceramic such as .alpha.-tricalcium phosphate as the base
cementing powder to increase the surface pH of the setting cement.
The present invention seeks to provide bioresorbable calcium phosphate
cements which can be used as hard tissue replacement materials. These
cements can be moldable at the surgical site with reasonable setting time
or can be prepared as premolded shapes. The basic constituent of the
cement is the strongly alkaline tetracalcium phosphate, and the setting
reagents are citric acid or the combination of acidic citrate compounds
with other soluble biocompatible salts. To control the bioresorption rate,
a variety of biocompatible compounds can be added as filler for these
cements.
These cements are only slightly acidic during the beginning of setting.
After setting, the surface pH of the cements raises rapidly to near 7 or
higher in a rather short period in the liquid environment. During
dissolution, the cements form only constituents or ions which are also the
compositions of the body fluid. Advantages of these cements are relative
high surface pH, good biocompatibility, bioresorbability, reasonable
setting time and good manipulation character. These cements would be very
useful as implants for hard tissue replacement materials. They can be used
for bone grafts, bone defect fillers, dental cements and bone cements.
They can also be used as binder system for granule hydroxyapatite and as a
drug delivery system.
As aspect of this invention is a cementitious paste for orthopaedic and
dental applications comprising:
a cementing powder selected from the group consisting of tetracalcium
phosphate;
a setting reagent selected from a group consisting of citric acid,
NaH.sub.2 citrate, and Na.sub.2 H citrate, wherein the Weight ratio of
cementing powder to setting reagent ranges from 2:1 to 15:1; and
sufficient water to form a paste, and which paste, after setting, has a pH
greater than 5.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Among the calcium phosphate salts, the monocalcium phosphate is acidic
while the aqueous suspensions of dicalcium phosphate, tricalcium phosphate
or hydroxyapatite show near neutral pH. The only calcium phosphate ceramic
which shows strong alkaline character is tetracalcium phosphate. By using
this ceramic as cement powder, it can release hydroxide ion to neutralize
the acidic setting reagent immediately. Even after setting, the excess
unreacted powder can still leach hydroxide ion resulting in a rapid
increase of the surface pH to near neutral or higher.
By reacting the calcium phosphate salt, having a Ca/P mole ratio equal to
1.5 or higher, with polyfunctional organic acids, the calcium phosphate
salt will dissolve and form dicalcium phosphate and the corresponding
calcium organic salts during the setting stage. The extent of the
reaction, the setting time and the setting character are sensitive to the
nature of cement powder, the pH and the type of setting reagent. For
example, the dissolution rate of calcium phosphate salts having a mole
ratio of 1.5 or higher of Ca/P follows the order; tetracalcium phosphate
>.alpha.-tricalcium phosphate>.beta.-tricalcium phosphate >hydroxyapatite.
By using citric acid as the setting reagent, both tetracalcium phosphate
and .alpha.-tricalcium phosphate can form good setting cements in a rather
short time. In contrast, both hydroxyapatite and .beta.-tricalcium
phosphate, because of their slow dissolution rate, cannot form a good
setting cement with citric acid.
A further increase of the surface pH of the setting cement is made by using
hydrogen citrate salt or citric acid with alkaline reagents instead of
using pure citric acid as setting reagent. Among the suitable hydrogen
citrate salts used are sodium dihydrogen citrate, ammonium dihydrogen
citrate or potassium dihydrogen citrate. Also useful as pH modifiers are
NaOH, KOH, NH.sub.4 OH, Sodium citrate potassium citrate, ammonium
citrate, sodium phosphate, disodium hydrogen phosphate, potassium
phosphate, and dipotassium hydrogen phosphate. If the combination of
citric acid and alkaline reagents is used, the combined reagents solution
can be adjusted to have pH values ranging from approximately 3 to 5. The
pH of a concentrated pure citric acid stays normally near 2. In contrast,
the above setting reagent should provide an initial solution pH which is
much higher than the pure citric acid. After setting, surface pH of the
setting cement will stay near 5 and raises to near neutral or higher in a
rather short period.
Another concern of the implantable cement as hard tissue replacement
material is the bioresorption rate of the cement. A single component
cement system such as Plaster of Paris would lack the flexibility in
controlling the bioresorption rate. When the setting Plaster of Paris is
implanted, it resorbs too fast to match the bone growth. In the present
cementing system, the weight ratio of calcium phosphate cementing powder
to the setting reagent stays at least 2 or higher. The ratio can raise to
as high as 15. Therefore, the final setting cement contains the reaction
products and considerable amount of un-reacted calcium phosphate. Both
reaction products and the un-reacted calcium phosphate ceramics such as
tetracalcium phosphate and tricalcium phosphate are bioresorbable.
In order to meet specific need for controlling the bioresorption rate, a
biocompatible material in the form of fine powder or granule, having
particle size ranging from 1 micron to 20 mesh, is used as filler for the
cementing system. Beside having a good biocompatibility, the filler should
not show significant effect on the integrity and setting behavior of the
cement. These useful fillers include tricalcium phosphate, calcium
phosphate apatite, dicalcium phosphate, calcium carbonate, calcium sulfate
dihydrate, calcium sulfate hemihydrate, calcium sulfate anhydrous, calcium
fluoride, calcium oxide, calcium citrate, magnesium hydroxide, magnesium
oxide and other sparingly soluble calcium organic salts.
In the present invention of calcium phosphate cements, the cementing powder
was premixed with filler material to form a homogeneous mixed powder. The
setting chemicals can be prepared by two methods: 1) dissolving the
setting reagent in water or saline water to form an aqueous setting
solution; or 2) premixing the solid setting reagents with the cementing
powder, and using sterilized pure water or saline water as the setting
aqueous solution.
The cements of present invention may be used as bioresorbable cement or
cements for: 1) bone grafts, bone defect filler or replacement of bone
that has been removed surgically or due to trauma; 2) material for ridge
augmentations; 3) jaw repairs; 4) cranial and maxillofacial surgeries; 5)
luting cement in dentistry and orthopaedic surgery; 6) spinal fusions; 7)
endodontic filling material; 8) root cement; 9) replacing or promoting
regeneration of bone mineral lost due to periodontal disease; and 10) drug
release systems. Antibiotics are the preferred drugs to be released by the
cement of this invention.
The strength as well as the setting time of the present cements depends
strongly on the nature and particle size of the calcium phosphate and the
filler powder, the type and amount of the setting reagent, and the solid
powder to liquid ratio. In general, by keeping other factors the same, the
strength normally increases by reducing the particle size of the powder.
The setting time increases with decreasing the cement powder to setting
reagent ratio.
The cement can be pre-set to any shape before use. For example, in the use
as a drug delivery system, the required amount of the drug is mixed with
the cementing powder and setting reagent to form paste first. After set
time, the hardened cement may be broken into a suitable size of granule
form. This drug containing cement is then dried and stored before use. For
more convenient application, the cement can be prepared in the surgical
site as paste first. During this stage, the pasted can be introduced into
the bone defects or implantation site before it becomes hardening.
EXAMPLE 1
The pure tetracalcium phosphate prepared by solid state reaction was ground
to 270 mesh. 2 g of the powder was mixed with 0.3 g of anhydrous citric
acid. The mixed powder was then further mixed with 0.7 ml pure water to
form a thick sticky paste. This prepared paste set within several minutes.
Shortly after set, surface pH of the setting cement was tested with pH
indicator paper. The surface pH was higher than 5. This hardened paste was
then aged in pure water, and it did not show any sign of disintegration.
EXAMPLE 2
Pure hydroxyapatite ceramics was decomposed by high temperature treatment
to form o-tricalcium phosphate and tetracalcium phosphate by the following
reaction
Ca.sub.10 (PO.sub.4).sub.6 (OH).sub.2 .fwdarw.2 Ca.sub.3 (PO.sub.4).sub.2
+Ca.sub.4 P.sub.2 O.sub.9 +H.sub.2 O
2 g of the above decomposed product was then mixed with 0.3 g of anhydrous
citric acid. The mixed powder was then mixed with less than 1 ml of water
to form a sticky paste. This paste became hardened within several minutes
and resisted disintegration in an aqueous environment. If the
decomposition of hydroxyapatite is carried out under vacuum at lower
temperature, the decomposed products would be .beta.-tricalcium phosphate
and tetracalcium phosphate. This decomposed product can also be used to
replace tetracalcium phosphate as cementing powder.
EXAMPLE 3
In examples 1 and 2, the setting reagent used was pure citric acid. In
order to reduce the acidity of the setting reagent, the acidic citrate
salts such as NaH.sub.2 Citrate, Na.sub.2 HCitrate, KH.sub.2 Citrate,
K.sub.2 HCitrate and the corresponding acidic ammonium citrate salts can
be used to replace citric acid as the setting reagent. For example, 2 g of
pure tetracalcium phosphate was premixed 0.3 g NaH.sub.2 Citrate first.
This premixed powder was then intermixed with enough water to form a
homogeneous mixed paste. After several minutes, the paste hardened. In
other cases, Na.sub.3 PO.sub.4, Na.sub.2 HPO.sub.4, K.sub.2 HPO.sub.4,
Na.sub.3 Citrate, K.sub.3 Citrate can be used together with citric acid as
a setting reagent which has higher pH than pure citric acid.
EXAMPLE 4
In examples 1 to 3, the cementing calcium phosphate cementing powder was
premixed with the required setting reagent. The mixed powder was then
intermixed with pure water to form cement. For storage and sterilization
purpose, the above setting reagents such as citric acid, acidic citrate
salts or pH adjusting salts can be dissolved in pure water to form a
aqueous setting solution. The calcium phosphate cementing powder was then
mixed with the setting solution to form a paste. For example, 1.5 g of
citric acid and 1.5 g of trisodium citrate was dissolved in 5 ml pure
water first to form an aqueous setting solution. 2 g of fully decomposed
hydroxyapatite which contains mainly .alpha.-tricalcium phosphate and
tetracalcium phosphate was then mixed with about 0.8 ml of the above
solution to form a paste. After mixing, the paste becomes hardened within
several minutes.
EXAMPLE 5
In examples 1 to 4, the used of pure tetracalcium phosphate or fully
decomposed hydroxyapatite as cementing powder to form moldable cement has
been demonstrated. In order to meet a specific bioresorption rate, certain
types of fillers can also be incorporated into this cementing powder
system. Suitable fillers are calcium carbonate, calcium fluoride, calcium
sulfate dihydrate, calcium sulfate hemihydrate, calcium sulfate anhydrous,
calcium citrate, dicalcium phosphate, tricalcium phosphate, octacalcium
phosphate, calcium phosphate apatite, magnesium oxide, magnesium hydroxide
or biocompatible insoluble calcium organic salts. The maximum amount cf
fillers which can be used depends strongly on the activity and particle
size of the filler. With fine particle size of inert filler, about 50% to
60% of the total weight of the cement powder can be inert filler. For
large particle sizes such as granule form of filler, the filler which can
be incorporated is about 75% of the total weight of the calcium phosphate
cementing powder. For special active filler such as .alpha.-tricalcium
phosphate which is also involved in the cementing reaction, the amount
incorporated can be as high as 90%. For example, 1 g of citric acid and 1
g of trisodium citrate was dissolved in 5 ml pure water to form a setting
solution. 1 g of tetracalcium phosphate powder and 1 g of calcium sulfate
anhydrous powder was mixed first. The mixed powder was then mixed with
about 0.7 ml of the above setting solution to form a paste. This paste
hardened within 5 minutes.
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